DESCRIPTION: (Applicant's Abstract) The past several years have seen an alarming increase in the abuse of centrally acting sympathomimetic stimulants and an increase in the incidence of cardiovascular toxicity. Due to the close temporal relationship between drug use and the onset of most clinically significant toxicities, most reports of the cardiovascular effects of these drugs have focused on the acute toxic responses. Very little attention has been paid to the possibility that repeated stimulant use may alter cardiovascular function in such a way as to increase the potential for the development of serious cardiovascular toxicity. Therefore, this proposal was designed to test the hypothesis that the repeated administration of sympathomimetic stimulants produces structural and/or functional changes in the cardiovascular system that increase the potential for the development of serious cardiovascular toxicity. These studies will attempt to determine whether the repeated administration of cocaine, 3,4-methylenedioxymethamphetamine (MDMA) or methamphetamine (METH) alters arterial pressure, heart rate, electrocardiographic activity size and baroreceptor or Bezold-Jarisch reflex function. Histologic and morphometric analysis will also be performed to determine whether repeated stimulant administration produces damage or structural changes in the heart that are visible at the light or electron microscopic level. Two types of dosing schedules will be employed. One will involve administration of cocaine, METH or MDMA on a daily basis for up to 2 months. The other type of schedule will involve large, closely spaced doses given for 4-14 days. The latter types of stimulant dosing schedule is similar to those often used to produce neurotoxicity in monoaminergic systems. The proposed studies represent a unique combination of "state of the art" techniques for cardiovascular recording in conscious animals and histological analysis to examine the changes in cardiac, cardiovascular and cardiovascular reflex structure/function elicited by the repeated administration of sympathomimetic stimulants. Examination of these changes should provide new insight into the potential for repeated stimulant use to produce cardiac and/or cardiovascular toxicity. The mechanisms mediating these changes will provide the basis for future studies.